(+)-Asimicin (1) and (+)-bullatacin (2)--bis-tetrahydrofuranyl, 4-hydroxylated, Armonaceous acetogenins--represent two of the structurally most complex and biologically potent members of this abundant family of antitumor and pesticidal natural products. (+)-Bullatacin possesses remarkable levels both of cytoxicity against many human rumor cell lines, a feature shared by a number of the 4-hydroxylated acetogenins, and in vivo antitumor activity. For example, see J. K. Rupprecht et al., J. Nat. Prod., 53, 237 (1990); X. Fang et al., Phytochem. Anal., 4, 27 and 49 (1993); and K. Ahammadsahib et al., Life Sci., 53, 1113 (1993). (+)-Bullatacin and (+)-asimicin interfere with mitochondrial electron transport processes by interaction with complex I. See, M. Landers-Hausen et al., Pestic. Sci., 33, 427 (1991), M. Espositi et al., Biochem. J., 301, 161 (1994) and M. A. Lewis et al., Pesticide Biochem. Physiol., 45, 15 (1993).
The relative configurations within the bis-THF portions of asimicin and bullatacin were deduced by application of the .sup.1 H NMR chemical shift correlation method developed for uvaricin. (T. Hoye et al., J. Amer. Chem. Soc., 109, 4402 (1987); X. -P. Fang et al., Heterocycles, 32, 11 (1991) Y. -H. Hui et al., J. Nat. Prod., 52, 463 (1989). Details of the entire relative and absolute stereostructure of (+)-asimicin (1) and (+)-bullatacin (2) were unraveled only recently following extensive analysis of Mosher esters of the natural products, by M. J. Rieser et al., J. Amer. Chem. Soc., 114, 10203 (1992); and T. R. Hoye et al., Tet. Lett., 34, 5043 (1993). The structures of these compound are depicted below: ##STR1##
Three syntheses of bis-tetrahydrofuranyl (THF) Annonaceous acetogenins or their stereoisomers have been described. (T. R. Hoye et al., J. Amer. Chem. Soc., 113, 9369 (1991); T. R. Hoye et al., Tet. Lett., 34, 5043 (1993); and U. Koert et al., Tett. Lett., 35, 2517 (1994)). However, the majority of efforts to date have focused on the simpler mono-THF acetogenin targets. For example, see B. Figadere et al., Tett. Lett., 33, 5189 (1992); Z. -J. Yao et al., Tett. Lett., 35, 157 (1994); H. Makabe et al., J. Chem. Soc. Perkin Trans. I, 1975 (1994); and B. M. Trost et al., J. Amer. Chem. Soc., 116, 7459 (1994).
Therefore, a need exists for efficient methods to synthesize the Annonaceous acetogenins and their analogs, particularly those which comprise the (C4)-hydroxyl group.